1. Field of the Invention
The present invention relates to the analysis of biomarkers in cerebrospinal fluid (CSF). More particularly, the present invention relates to (1) discovering the importance of correcting CSF biomarker levels for their dilution in CSF and (2) correcting CSF measures for their dilution using a semi-automated procedure for determining CSF volumes in patients with variable and disease-related increases in CSF volume. This invention is important for diagnosing and monitoring the course of Alzheimer's disease, but the scope of the invention reaches far beyond diagnosing and monitoring of Alzheimer's disease. For example, the invention can be applied to monitor other disorders, such as vascular dementia, boxer's syndrome, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and stroke, just to name a few.
2. Description of the Related Art
Cerebrospinal Fluid (CSF) is a liquid that fills the ventricles of the brain and the spaces between arachnoid matter and pia matter of the brain and spinal cord. As the CSF is in contact with the brain, it has been known for some time that Alzheimer's Disease and other dementia-related illnesses can be diagnosed (and the progression of the illness monitored) by analyzing biomarkers in the CSF.
In addition, as more progress is made in the development of drugs that inhibit/slow down the progression of Alzheimer's Disease, analyzing the biomarkers can be used to evaluate the effectiveness of a drug on a particular patient, or group of patients.
However, heretofore, the process for analyzing biomarkers in CSF has been slow, cost prohibitive, and has not always provided accurate results. In fact, the sometimes inaccurate results of the prior art can hinder research and development of effective drugs, as well as increase the likelihood that a proper diagnosis of a particular illness may not be made in a timely fashion, or not at all for that matter.
One of the biomarkers of interest has been for some time, the tau protein and related forms thereof. In general, tau proteins are constituents of the neuronal axons. Under conditions of neuronal and synaptic degeneration, as is found with the progression of Alzheimer's Disease, the amount of tau protein in the CSF increases. Surgical research studies for non-Alzheimer related reasons have shown that the ventricular derived CSF concentration of tau (a protein found in all people) is two-fold higher than in the lumbar spinal tap derived CSF which is used for diagnostic purposes.
Lumbar spine derived CSF tau levels are elevated in the early stages of Alzheimer's Disease, perhaps before dementia is even noticeable or detectable in a clinical setting. However, longitudinal studies have reported that both in cases of mild cognitive impairment (MCI), as well as Alzheimer's, tau levels, as well as CSF amyloid beta 1-42 (Aβ42) levels, a marker for the fibrillar amyloid that is deposited in Alzheimer's disease in the form of senile plaques, do not significantly change over time in deteriorating patients.
The present inventors submit that the surprising result regarding the lack of a significant change in the above-mentioned biomarkers is likely the result of a disease-related increase in the size of the brain's CSF compartment, a compensatory response to the loss of brain tissue. In other words, the amount of CSF increases to compensate for reduced brain volume thus diluting the absolute amount of the biomarker thus causing the afore-mentioned biomarkers in the CSF to remain at similar levels, masking the amount of neuronal deterioration that has taken place when comparing a series of test results taken over time, or compared against predetermined concentration values.
Heretofore, neuroimaging methods have not been used to correct the diluted CSF biomarker. The prior art methods using MRI scans to calculate the CSF compartment heretofore have been cost prohibitive because of the need for highly trained persons to spend sometimes as much as several hours to calculate CSF volume for a single patient by methods that require manual identification and dissection of areas of the brain, with the ventricular size and other CSF containing structures being determined by the number of pixels counted in each of the areas identified. In particular, defining the anatomical boundaries of the ventricular system from MRI scans is complex and time consuming. The MRI scans can number as many as fifty or more “slices” of the ventricle being scanned, thus making the calculations a rather tedious procedure, and subject to error even by highly trained personnel. The prior art has had attempts to provide a semi-automated program to measure the whole brain CSF, but there was absolutely no disclosure, suggestion or motivation that the determination of ventricular size could be used to correct biomarkers in CSF volumes. Accordingly, a more reliable and less expensive way to perform such testing is needed in the art.